The present invention relates to certain novel dihydro- and tetrahydronaphthyridines useful for sensitizing tumor cells to the lethal effects of DNA-damaging agents such as ionizing radiation and chemotherapeutic agents.
Extensive evidence indicates that the radioresistance of many solid tumors is directly proportional to their hypoxic fractions. In the presence of oxygen the amount of cell kill achievable by ionizing radiation is increased.. When well oxygenated cells are irradiated, irreparable lesions occur resulting from the reaction between radiation-damaged DNA and oxygen. Under hypoxic conditions such as those found in solid tumors, the initial damage that occurs from ionizing radiation is more readily repaired than that which occurs in oxic cells and ultimately leads to tumor regrowth.
The presence of hypoxic cells in tumor tissue has been demonstrated repeatedly in animal tumors, and their presence results in resistance to radiation, which makes cures with a single dose of x-rays difficult or impossible. (See Adams GE, et al, Chemotherapy 1975;7:187-206, Plenum Press, New York.) This problem is compounded by the fact that radiotherapy continues to be a major method for treating cancer patients. Approximately 50% to 60% of all cancer patients undergo some type of radiotherapy. However, the presence of these radio-resistant cells results in about 30% of these patients succumbing to a lack of control of the primary disease. Therefore, a need exists for a compound which renders solid tumors more susceptible to the lethal effects of radiation.
To overcome the problem of the resistance of hypoxic tumor cells to radiation therapy, patients have been irradiated in hyperbaric oxygen chambers. Although much experience has been gathered with this method, it is cumbersome and slow to use. Moreover, the shutdown of blood vessels is also a serious problem associated with this method.
Another solution which has been tried is the use of chemical agents which simulate the action of oxygen in their ability to sensitize hypoxic tumor cells to radiation. In 1963, Adams, et al (Biochem Biophy Res Comm 1963;12:473), proposed that the ability of compounds to sensitize hypoxic bacterial cells is directly related to their electron affinity. This idea has been generally verified and has aided the search for more active compounds.
In 1973, J. L. Foster and R. L. Wilson (Brit J Radiol 1973; 46: 234) discovered the radiosensitizing action of the antiprotozoal drug metronidarole (2-methyl-5-nitro-1H-imidazole-1-ethanol). Metronidazole is active both in vitro and in vivo as a radiosensitizer.
Another antiprotozoal drug, misonidazole (.alpha.-(methoxymethyl)-2-nitro-1H-imidazole-1-ethanol) has also recently proven to be of value as a radiosensitizer for hypoxic tumor cells (Asquith J, et al, Rad Res 1974;60:108).
Both metronidazole and misonidazole are effective as radiosensitizers for hypoxic cells in vivo. However, both compounds exhibit serious adverse central nervous system (CNS) side effects when administered to mice. They exhibit peripheral neuropathy effects and convulsions in mice and their CNS toxicity is thus a limiting factor for their use in humans. Nevertheless, the activity of these compounds as radiosensitizers has led to further interest and has spurred the search for additional compounds with similar activity but with diminished side effects.
Radiotherapy is now routinely given as a series of small doses of radiation (fractionated treatment) in an effort to minimize normal tissue damage and allow for tumor reoxygenation. This regimen renders the tumor more sensitive to successive radiation doses. However, substantial repair of radiation-induced damage can also occur between these small doses of radiation. This is illustrated by cell survival plots of nonexponential cell kill, which is sometimes referred to as the shoulder region of an x-ray dose-response curve (i.e., cells surviving the first dose of radiation respond as unirradiated cells to the second fraction, etc). The use of a fractionated regimen provides a small therapeutic gain with each fraction resulting in an improved gain over the course of the treatment. Inhibitors of this repair process, i.e., shoulder-modifying agents such as N-methylformamide, have been shown to sensitize tumors to the lethal effects of radiation.
Some cells when exposed to radiation do not immediately succumb to the lethal effects of radiation. This delay in toxicity, usually referred to as potentially lethal damage (PLD), accounts for some of the postirradiation toxicity that is seen when cells are treated with x-rays. PLD is DNA damage, which may be lethal if the cell attempts to replicate, but which is repaired if the cells are prevented from replicating. Compounds such as 3-aminobenzamide (PLDR inhibitors) have been shown to inhibit this postirradiation repair process, thereby sensitizing cells to the lethal effects of radiation.
Ben Hur, et al (Rad Res 1984; 97: 546), demonstrated that in certain cell lines the repair of damage caused by exposure to DNA-damaging agents such as ionizing radiation, was inhibited by 3-aminobenzamide. This inhibition of repair led to an enhanced killing of these cells by the damaging agents. The compounds examined are also inhibitors of poly (ADP-ribose) synthetase or adenosine diphosphate ribosyl polymerase (ADPRP), an enzyme that is elevated when cells are exposed to alkylating agents and to ionizing radiation, and is thought to play a role in the repair of DNA damage. Therefore, inhibitors of poly (ADP-ribose) synthetase can potentiate the lethal effects of DNA-damaging agents such as ionizing radiation and also potentiate for use in the methods of the present invention certain chemotherapeutic agents such as bleomycin (Kato T, Suzumura Y, Fukushima M, Anticancer Research 1988;8:239) and the like.
The present invention provides compounds which enhance the lethal effects of ionizing radiation thereby making tumors more sensitive to radiation therapy. These compounds work by affecting the processes involved in the repair of radiation-induced DNA damage. Since the compounds of the invention also inhibit poly(ADP-ribose)synthetase they have utility as potentiators of certain chemotherapeutic agents as described above by T. Kato, et al.
U.S. Pat. No. 07/758,180 (EPA 355750) discloses substituted dihydroisoquinolinones and related compounds as potentiators of the lethal effects of radiation and certain chemotherapeutic agents.
T. Sakamoto, et al. (Chem Pharm Bull 1986;34:2018-23) covers the iodination and subsequent dehydroxychlorination of 1, 6-naphthyridin-5 (6H) -one producing 5-chloro-8-iodo-1,6-naphthyridine which was converted to the 5-methoxy derivative.
E. Otiai and K. Miyaji (J Pharm Soc Japan 1938;58:764-70) and N. Ikekawa (Chem Pharm Bull 6:263-269) cover the synthesis of 1,6-naphthyridines.
Y. Combret, et al. (Tetrahedron 1991;47:9369) discuss a 1,6-naphthyridinone structure (see also Y. Combret, et al. (Chemistry Letters 1991;125-8)).
U.S. Pat. No. 4,329,349 covers certain 6-C.sub.1-4 alkyl-7-phenyl or substituted phenyl 1,6-naphthyridine-5(6H)-ones useful as muscle relaxants and as antiinflammatory agents.
V. I. Sigova and M. E. Konshin (Khim Geterot Soed 1984;783-5) covers a synthesis of substituted 5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridines by cyclization of substituted 2-styrylnicotinic acid amides.
K.-H. Nietsch and R. Troschutz (Arch Pharm (Weinheim) 1985;318:175-7) covers the preparation of 7,8-dihydro-1,6-naphthyridin-5 (6H) -ones.
M. Tada and Y. Yokol (J Heterocyclic Chem 9;26:45-8) covers the synthesis of tetrahydronaphthyridinone derivatives.
J. Baldwin, et al (J Org Chem 1978;43:4878-80) covers a naphthyridinone synthesis via enamine cyclization.